The negative effects of methamphetamine abuse and addiction on psychological and physical well-being are a major public health concern. Much effort to date has rightfully focused on the role of the brain's reward circuitry in mediating the behavioral and psychological effects of methamphetamine. While such studies have led to important insights into the mechanisms of methamphetamine addiction, the rate of relapse among abstinent methamphetamine abusers remains high. Hypersomnolence, characterized by excessive daytime sleepiness, is typical of early abstinent methamphetamine users. In normal individuals sleep is coupled to reduced cerebral glucose metabolism. In early abstinent methamphetamine users, hypersomnolence is paralleled by excessive glucose utilization in the brain. The neurobiological mechanism whereby methamphetamine alters sleep and cerebral metabolism is unknown. We posit that the previously documented suppression of a synaptic connectivity-related gene network in the brain (including the transcriptional regulator Egr3 and its target, the activity-regulated cytoskeleton-associated protein, Arc) by methamphetamine disrupts the neuroenergetic function of sleep. Our overarching hypothesis is that disruption of the sleep/wake- dependent dynamics of Egr3 and Arc expression by methamphetamine prevents sleep-dependent changes in glucose metabolism and electroencephalographic slow wave dynamics. Experimentation on Egr3-deficient mice, in which Arc expression is suppressed in a manner similar to chronic methamphetamine exposure, will allow us to address our working hypothesis for the proposed experiments: sleep/wake cycle-dependent dynamics of the Egr3/Arc transcriptional regulatory pathway is essential for the decline of cerebral glucose metabolism and sleep slow wave activity that define normal sleep/wake cycles. We propose two specific aims in which we will determine whether Egr3-deficiency modifies 1) sleep/wake cycle-dependent changes in sleep slow wave activity and cerebral glucose metabolism and 2) METH-induced suppression of sleep/wake cycle- dependent Arc expression. The anticipated results will establish a conceptual and experimental framework for future work by demonstrating a mechanistic link between changes in Egr3/Arc expression and sleep- dependent metabolic events. The proposed experiments are innovative, in our opinion, because they have the potential to identify a previously unrecognized impact of methamphetamine abuse on a fundamental brain function. The results are expected to collectively establish that chronic methamphetamine exposure disrupts the neuroenergetic function of sleep.